BRIEF COMMUNICATION

(0.5%) are the only ones with sporadic Aβ-CAA diagnosed

Early Onset Cerebral Amyloid at younger than 50 years. Informed consent was obtained
Angiopathy following from each patient.

Childhood Exposure to Case 1

Cadaveric Dura A 48-year-old man had 2 generalized tonic–clonic seizures
within 1 month. At age 11 years, a choroid plexus papil-
Gargi Banerjee, MRCP ,1 loma was treated by posterior fossa resection and a cadav-
Matthew E. Adams, FRCR,2 eric dural patch (1980) but no radiotherapy. There was
Zane Jaunmuktane, FRCPath,3,4 no family history of brain hemorrhage or cognitive impair-
G. Alistair Lammie, FRCPath,5 ment. Clinical examination revealed longstanding right
Ben Turner, MD,6 Mushtaq Wani, FRCP,7 arm mild pyramidal weakness and ataxia, and slightly
Inder M. S. Sawhney, DM,7 unsteady gait. Brain magnetic resonance imaging (MRI)
Henry Houlden, PhD,3 Simon Mead, PhD,8,9 showed patchy T2 hyperintensities bilaterally throughout
Sebastian Brandner, MD, FRCPath,4,10 and the cerebral white matter, and 5 punctate foci of restricted
David J. Werring, FRCP1 diffusion at the gray–white matter interface. Electroen-
cephalography demonstrated intermittent left anterior cen-
Amyloid-β transmission has been described in patients both trotemporal theta/delta activity enhanced by drowsiness
with and without iatrogenic Creutzfeldt–Jakob disease; and hyperventilation, with occasional sharp slow waves; he
however, there is little information regarding the clinical commenced levetiracetam. Carotid duplex, craniocervical
impact of this acquired amyloid-β pathology during life.
computed tomography (CT)-angiography, bubble-contrast
Here, for the first time, we describe in detail the clinical and
neuroimaging findings in 3 patients with early onset symp- echocardiography, and 24-hour electrocardiogram were
tomatic amyloid-β cerebral amyloid angiopathy following normal. Two months later, he developed confusion, dis-
childhood exposure to cadaveric dura (by neurosurgical orientation, and verbal slowing; brain MRI (Fig 1A–C)
grafting in 2 patients and tumor embolization in a third).
showed multifocal abnormal cortical signal and swelling
Our observations provide further in vivo evidence that cere-
bral amyloid angiopathy might be caused by transmission (with adjacent sulcal high signal) on T2-weighted
of amyloid-β seeds (prions) present in cadaveric dura and sequences, most conspicuously in the left frontal region
have diagnostic relevance for younger patients presenting (where there was associated leptomeningeal enhancement
with suspected cerebral amyloid angiopathy.
ANN NEUROL 2019;85:284–290
From the 1Stroke Research Centre, Department of Brain Repair and
Rehabilitation, University College London Queen Square Institute of
Neurology and National Hospital for Neurology and Neurosurgery, London;
2
Lysholm Department of Neuroradiology, National Hospital for

I t is hypothesized that amyloid-β (Aβ), a hallmark of Alz-

heimer disease and cerebral amyloid angiopathy (CAA),
is transmissible by a similar mechanism to acquired prion
Neurology and Neurosurgery, London; 3Department of Molecular
Neuroscience, University College London Queen Square Institute of
Neurology, London; 4Division of Neuropathology, National Hospital for
Neurology and Neurosurgery, London; 5Department of Pathology,
diseases.1 Initially described in iatrogenic Creutzfeldt– Cardiff University, Cardiff; 6Barts and London School of Medicine and
Jakob disease (iCJD),1–7 probable Aβ transmission in the Dentistry, Queen Mary University of London and Royal London Hospital,
London; 7Morriston Hospital, Abertawe Bro Morgannwg University
absence of iCJD has been reported following administra- Health Board, Swansea; 8Medical Research Council Prion Unit at
tion of cadaveric human growth hormone,3 childhood University College London, University College London Institute of
Prion Diseases, London; 9National Prion Clinic, National Hospital
neurosurgery,8 and cadaveric dural graft insertion.9 How-
for Neurology and Neurosurgery, London; and 10Department of
ever, the clinical and neuroimaging findings, latency, and Neurodegenerative Disease, University College London Queen Square
range of potential exposure mechanisms for Aβ transmis- Institute of Neurology, London, United Kingdom
Address correspondence to Dr Werring, Stroke Research Centre, Depart-
sion remain uncertain.
ment of Brain Repair and Rehabilitation, UCL Queen Square Institute of
We describe 3 patients diagnosed with symptomatic Neurology, Russell Square House, 10-12 Russell Square, London WC1B
early onset CAA in a specialist intracerebral hemorrhage ser- 5EH, United Kingdom. Email: [email protected]

vice, all with previous childhood neurosurgical or neurovas- Received Sep 8, 2018, and in revised form Nov 21, 2018. Accepted for
cular procedures using cadaveric dura. Of 663 individual publication Dec 22, 2018

patients referred since January 1, 2015, the 3 described View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.25407.

284 © 2018 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduc-
tion in any medium, provided the original work is properly cited.
 Banerjee et al.: Banerjee: Early Onset CAA

FIGURE 1: Brain imaging findings. (A–D) Case 1. Fluid-attenuated inversion recovery (FLAIR; A), T1-weighted postgadolinium (B),
and diffusion-weighted imaging (C) axial images acquired 2 months after initial presentation demonstrate left frontal gyral
swelling and abnormal sulcal signal (arrow in A) with leptomeningeal enhancement (B) and a punctate focus of restricted
diffusion (arrowhead). (D) Susceptibility-weighted imaging 4 months later shows a lobar hemorrhage (arrow), multifocal
superficial siderosis, and multiple microbleeds. The ventriculomegaly observed in C and D is longstanding (since the choroid
plexus papilloma). (E–H) Case 2. (E, F) Susceptibility-weighted imaging shows hematomas in both frontal lobes (arrows) and
widespread superficial siderosis and microbleeds, visible as a band of low signal following the leptomeningeal surface of the
brain and peripheral, punctate foci of low signal, respectively. (G) 18F-Florbetapir positron emission tomographic (PET)–
computed tomographic (CT) imaging shows increased uptake in frontal and parietal cortex (standardized uptake value [SUV]
range = 0.0–2.8), suggestive of amyloid deposition (arrows). The 2 areas without uptake (arrowheads) correspond with areas of
old hemorrhage, as seen on axial CT (H). (I–L) Case 3. FLAIR coronal (I) and T1-weighted postgadolinium axial (J) images
15 months after initial presentation showing abnormal gyral and sulcal signal in the left temporal lobe (arrow) with associated
leptomeningeal enhancement. (K) Susceptibility-weighted imaging 5 months later showing hemosiderin deposition due to
previous lobar hemorrhage and numerous temporal microbleeds. (L) Merged 18F-florbetapir PET-CT imaging shows increased
uptake (SUV range = 0.0–3.4) in frontal and posterior (parietal and occipital) cortical regions (arrows); the area with reduced
uptake (arrowhead) corresponds to the area of old hemorrhagic damage. [Color figure can be viewed at www.
annalsofneurology.org]

and recent subarachnoid hemorrhage) and several new intracerebral hemorrhage) showed 680 red blood cells and
punctate foci of restricted diffusion. Gradient-recalled elevated protein (0.99 g/l). The patient received intrave-
T2*-weighted sequences showed left parietal superficial nous methylprednisolone 500 mg daily for 5 days fol-
siderosis and several peripheral microbleeds. A lumbar lowed by oral prednisolone (50 mg) for a presumed
puncture (performed prior to any clinically manifest diagnosis of primary central nervous system vasculitis,

February 2019 285

ANNALS of Neurology

without clinical response. Three months later, the patient had gyrus, multifocal superficial siderosis, and numerous strictly
an acute left frontal intracerebral hemorrhage causing sudden lobar cerebral microbleeds (see Fig 1D).
aphasia. Brain biopsy demonstrated leptomeningeal and cor-
tical CAA with scattered leptomeningeal hemosiderin Case 2
deposits and widespread diffuse parenchymal Aβ deposits, A 39-year-old man presented with multiple intracerebral
but no perivascular inflammation, vasculitis, or fibrinoid hemorrhages. His past medical history included partial re-
degeneration (Fig 2A, A1, A2); there was no tau pathology or section of a left parotid cavernous hemangioma at age
abnormal prion protein (PrP) deposition. APP, PSEN1, and 2 years followed by external carotid embolization using
PSEN2 gene testing was negative for mutations causing lyophilized cadaveric dura and “gelfoam” emboli (1981).
Alzheimer disease or CAA. APOE genotype was ε3/ε3. A procedural ischemic stroke, likely secondary to internal
Follow-up MRI 6 months later showed partial resolution of carotid embolism, caused right arm weakness. At age
the left frontal swelling and meningeal enhancement, new 6 years, the patient had further embolization and paroti-
parenchymal hemorrhage in the posterior left inferior frontal dectomy. He remained well until age 27 years, when he

FIGURE 2: Brain biopsy findings. (A–A2) In Case 1, there is leptomeningeal and cortical cerebral amyloid angiopathy, and
widespread diffuse parenchymal amyloid-β (Aβ) deposits (A and A1). There is only minimal parenchymal and perivascular
microglial and macrophage activity (A2). (B–B2) In Case 2, there is particularly widespread leptomeningeal and cortical amyloid
angiopathy, including vessel wall splitting (B, red arrows) and capillary amyloid angiopathy in the cortex (B1, blue arrows). In the
cortex, there are also diffuse parenchymal Aβ deposits and rare plaques with central amyloid cores (B, black arrows). There are
abundant perivascular macrophages, some laden with hemosiderin (B2). Sections A, A1, B, and B1 are immunostained for Aβ; A2
and B2 are immunostained for CD68. All sections are counterstained with hematoxylin. Scale bar = 500 μm in A and B; 50 μm in
A1; 100 μm in B1, and 200 μm in A2 and B2. [Color figure can be viewed at www.annalsofneurology.org]

286 Volume 85, No. 2

 Banerjee et al.: Banerjee: Early Onset CAA

had 3 generalized tonic–clonic seizures associated with a revealed subtle nonspecific vascular abnormalities around
left frontal intracerebral hemorrhage. After treatment with the craniectomy. Imaging 3 months later showed an acute
carbamazepine, he remained seizure-free for 4 years but left superior parietal hemorrhage. Repeat DSA showed no
then had a left frontal lobe intracerebral hemorrhage caus- new vascular abnormalities. MRI performed 15 months
ing disorientation. He subsequently experienced persistent later showed regression of the left temporal hematoma,
memory impairment and intermittent confusion with fur- and mild gyral swelling in the temporal and parietal paren-
ther intracerebral hemorrhages at age 33 years (right parie- chyma with abnormal sulcal fluid-attenuated inversion
tal) and 35 years (left occipital and right frontal). There recovery signal, local leptomeningeal enhancement, and
was no relevant previous medical or family history. Clini- additional microbleeds (see Fig 1I–K). 18F-Florbetapir
cal examination revealed longstanding right hemiatrophy amyloid PET demonstrated widespread cortical amyloid
and mild right arm pyramidal weakness. Brain MRI deposition (see Fig 1L). CSF analyses (performed >1 year
revealed chronic and recent lobar hematomas, patchy after the patient’s symptomatic hemorrhage) showed low
superficial siderosis, and innumerable lobar microbleeds (see Aβ1-42 (251 pg/ml, normal range = 627–1,322 pg/ml),
Fig 1E, F). 18F-Florbetapir amyloid positron emission low total tau (81 pg/ml, normal range = 146–595 pg/ml)
tomography (PET) showed widespread moderate cortical and phospho-tau (13 pg/ml, normal range = 24 to
amyloid deposition (see Fig 1G, H). Cerebrospinal fluid 68 pg/ml), but normal 14-3-3 and S100β. Next genera-
(CSF) examination, performed>1 year after the last symp- tion sequencing for mutations in genes associated with
tomatic intracerebral hemorrhage (although contemporane- dementia (including APP, CHMP2B, CSF1R, FUS, GRN,
ous MRI showed evidence of clinically silent HTRA1, ITM2B, MAPT, NOTCH3, PRNP, PSEN1,
macrohemorrhage), showed low Aβ1-42 (261 pg/ml, nor- PSEN2, TARDBP, TREM2, TYROBP, and VCP)10 was
mal range = 627–1,322 pg/ml) and normal total tau, tau/Aβ negative. APOE genotype was ε3/ε3. Repeat MRI, per-
ratio, 14-3-3 protein, and S100β. Next generation sequenc- formed 20 months after initial presentation, showed fur-
ing for mutations in genes associated with dementia (includ- ther accumulation of microbleeds.
ing APP, CHMP2B, CSF1R, FUS, GRN, HTRA1, ITM2B,
MAPT, NOTCH3, PRNP, PSEN1, PSEN2, TARDBP,
TREM2, TYROBP, and VCP)10 was negative. APOE geno- Discussion
type was ε2/ε3. After 2 further intracerebral hemorrhages, Our report describes early onset CAA occurring decades
brain biopsy confirmed widespread severe leptomeningeal after childhood neurosurgical or vascular procedures
and cortical CAA with parenchymal capillary CAA (see involving cadaveric dural material, providing further evi-
Fig 2B, B1), several cortical microvascular lesions, superfi- dence that Aβ might be transmissible as a prion. Further-
cial cortical siderosis, and perivascular hemosiderin-laden more, we provide new evidence that Aβ seeds might also
macrophages (see Fig 2B2) but no perivascular lymphocytic be transmitted via the intravascular route. Finally, in our
inflammation. There were moderate diffuse parenchymal patients the diagnosis of “iatrogenic” early onset CAA was
Aβ deposits and occasional core plaques but no tau pathol- made in vivo, and, in 2 cases, initially without brain
ogy or abnormal PrP deposition. biopsy, on the basis of brain MRI, CSF, and amyloid
PET findings.
The characteristic clinicoradiological presentation
Case 3 should help guide noninvasive diagnosis in at-risk individ-
A 34-year-old woman presented with severe generalized uals; all patients had prominent recurrent generalized
headache and right-sided visual field loss. Head CT tonic–clonic seizures at or shortly after presentation, and
showed acute left parieto-occipital intracerebral hemor- 2 of 3 had abnormal cortical and sulcal signal change—
rhage. Two months later she developed generalized tonic– both atypical features in sporadic late onset CAA. This lat-
clonic seizures, treated with levetiracetam. Examination ter imaging finding is similar to changes observed in
revealed mild ideomotor apraxia only. The patient had a patients with the inflammatory variant of CAA (CAA-
significant head injury causing a left parietal skull fracture related inflammation),11,12 which is thought to occur as a
at age 4 weeks; post-traumatic focal epilepsy was treated consequence of spontaneously generated anti-Aβ autoanti-
with phenobarbitone and later carbamazepine. At age bodies13 and bears a close resemblance to the amyloid-
3 months, a growing fracture was treated by left parietal related imaging abnormalities (ARIA) that can occur after
craniectomy and cadaveric dural repair (1982). treatment with anti-Aβ immunotherapy.14 Both ARIA
Brain MRI performed a few weeks after her intrace- and CAA-related inflammation can be either mildly symp-
rebral hemorrhage showed several left temporal lobar tomatic or asymptomatic,15–17 leading to speculation that
microbleeds. Digital subtraction angiography (DSA) this might represent physiological attempts at Aβ

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ANNALS of Neurology

clearance.18 Although we cannot confirm that this mecha- between 1982 and 1986.25 It is worth noting that lyophi-
nism is relevant in our patients, it raises the interesting lized cadaveric dura has also previously been used for non-
possibility that Aβ from exogenous dural material might neurosurgical (for example, head and neck, cardiothoracic,
be recognized as nonautologous and thus provokes a more abdominal, and urological19,20,25) procedures.
marked immune response. We acknowledge important limitations. We lack
In keeping with the few previous reports,8,9 our comprehensive information about the transplanted dura
patients first developed neurological symptoms approxi- (for example, batch or manufacturer details), so cannot
mately 3 to 4 decades after exposure to cadaveric dura establish causality, or prove that transplanted dura con-
(range = 27–37 years), suggesting a long incubation tained Aβ seeds. We cannot reliably estimate the popula-
period. The association between CAA and endovascular tion exposed to cadaveric dura potentially containing Aβ
embolization with cadaveric dura suggests that Aβ seeds seeds, because information on patients receiving a dura
might be transmitted without direct neurosurgical brain mater graft in the United Kingdom is not available, as
exposure. Lyophilized cadaveric dura embolization mate- noted above. We lack pathological proof that the patient
rial has been suggested to potentially transmit iCJD,19,20 described in Case 3 does not have iCJD, but the imaging
and experimental intravenous injection of Aβ seeds causes findings (with 90% sensitivity26), negative CSF 14-3-3
CAA.21 In 2 of our cases (Cases 1 and 2), there was evi- (with 80% specificity27), and absence of relevant symp-
dence of significant amyloid angiopathy distant from the toms strongly argue against this diagnosis. We were also
site of presumed transmission; this is in keeping with pre- unable to test for amyloid precursor protein (APP) dupli-
viously reported cases of suspected iatrogenic CAA, where cations in our patients, which are associated with early
widespread disease is observed on neuropathological exam- onset Alzheimer disease together with CAA.28,29 However,
ination.8,9 There are 2 potential explanations for these patients with APP duplications described to date have pre-
observations. First, although prions do spread along sented with progressive cognitive impairment, making this
defined neuroanatomical pathways, there is evidence that an unlikely cause of the clinical syndromes of the patients
they can reach specific target regions despite different ini- described here, who all had initial symptoms related to
tial sites of inoculation22; in the case of Aβ, the target intracerebral hemorrhages or seizures; additionally, there is
might be the cerebral and leptomeningeal vasculature, no evidence of a family history suggestive of APP duplica-
resulting in widespread disease of these vessels regardless tion for any of the cases described.28–33
of transmission method. Second, prions are believed to We also acknowledge that our cases might be prone
propagate in 2 stages, an exponential replication phase to ascertainment bias and are unlikely to represent the full
and a subsequent plateau phase where prion concentration spectrum of iatrogenic CAA. Our cases prompted further
is maximal.22 It is during this latter period that both clini- intensive investigation because of their relatively young
cal symptoms and visible neuropathology become mani- age at presentation; patients transplanted before the mid-
fest, and it has been hypothesized that this represents a 1970s or those transplanted after this time but at an older
“selective cellular vulnerability” to the high prion bur- age (as adults) would have presented at a typical age for
den22; if cerebral and leptomeningeal blood vessels are sporadic CAA (ie, >55 years), and thus are unlikely to
particularly susceptible to Aβ burden in this way, this have been investigated in the same detail. In the United
again could result in the widespread CAA observed. Kingdom, iCJD was described following dural transplanta-
In the United Kingdom, human dura mater grafts tion as early as 1969.34 However, 80% of cases of iatro-
were banned in 1992; information on patients receiving genic CJD identified worldwide were exposed between
dura grafts before this ban is not available,23 making it dif- 1983 and 198734; whether this is relevant to the narrow
ficult for us to estimate the risk of transmission. Although window of dural Aβ exposure seen in the patients
iatrogenic CJD following dural transplantation was associ- described here (1980–1982) is unknown. We cannot rule
ated with a single graft brand (Lyodura), it is not clear out the possibility of exposure of our patients to a “point
whether this will also be the case for Aβ; the situation is source”; 2 of our cases (Cases 1 and 3) were treated by the
further complicated as, compared to PrP, Aβ is relatively same operating surgeon at the same center, so it is con-
common. Although the number of dural grafts performed ceivable that samples came from a single donor or batch.
in the United Kingdom is unknown, there are data from However, Lyodura contains dura from different
other countries. In Japan, about 20,000 patents received donors34,35 so this common link between patients could
Lyodura grafts annually from 1983 to 1987, whereas in simply reflect the surgeon’s brand preference. With the
the USA, approximately 4,000 patients received dural benefit of hindsight, we now specifically ask all patients
transplants per year, of which <10% were Lyodura.24 In presenting with CAA about a prior history of surgical
Australia, 1,172 patients were exposed to Lyodura intervention, regardless of age, and we suspect that other

288 Volume 85, No. 2

 Banerjee et al.: Banerjee: Early Onset CAA

iatrogenic cases will come to light as a consequence. The 2 and Dr F. Fraioli for assistance with PET images for
identification of further cases, by our center and others, Figure 1.
will be essential for definitively establishing the nature and
extent of iatrogenic CAA, something that is beyond the Author Contributions
scope of this case series in isolation. G.B. and D.J.W. contributed to the conception and
We also recognize that CAA in our patients might design of the study; all authors contributed to the acquisi-
have resulted from mechanisms other than dural Aβ trans- tion and analysis of data; all authors contributed to draft-
mission. A recent neuropathological case series8 describing ing the text and preparing the figures.
Aβ transmission following childhood neurosurgery (n = 4)
reported that no dura was used in 1 case, and that its use Potential Conflicts of Interest
was unlikely (although not completely excluded) in the Nothing to report.
other 3, so our study cannot exclude transmission via neu-
rosurgical or neurovascular instrumentation. Additionally,
it is possible that brain trauma (either external insults
References
affecting the head or that secondary to neurosurgical
1. Jaunmuktane Z, Mead S, Ellis M, et al. Evidence for human transmis-
instrumentation) could impair perivascular clearance path- sion of amyloid-beta pathology and cerebral amyloid angiopathy.
ways for Aβ; indeed, associations between early onset Nature 2015;525:247–250.

CAA and traumatic brain injury have been described.8,36 2. Frontzek K, Lutz MI, Aguzzi A, et al. Amyloid-beta pathology and cere-
bral amyloid angiopathy are frequent in iatrogenic Creutzfeldt-Jakob
However, many of these cases also underwent neurosurgi- disease after dural grafting. Swiss Med Wkly 2016;146:w14287.
cal intervention and, in our series, case 2 had no prior his-
3. Ritchie DL, Adlard P, Peden AH, et al. Amyloid-beta accumulation in
tory of either direct head trauma or neurosurgical the CNS in human growth hormone recipients in the UK. Acta Neu-
intervention. ropathol 2017;134:221–240.

Our report increases the number of patients and 4. Cali I, Cohen ML, Haik S, et al. Iatrogenic Creutzfeldt-Jakob disease
with amyloid-beta pathology: an international study. Acta Neuro-
documented mechanisms of transmission for early onset pathol Commun 2018;6:5.
(“iatrogenic”) CAA, implicating the likely molecular
5. Kovacs GG, Lutz MI, Ricken G, et al. Dura mater is a potential source
mechanism of transmissible Aβ seeds (prions) in cadaveric of Abeta seeds. Acta Neuropathol 2016;131:911–923.
dura. The lengthy presymptomatic phase raises the possi- 6. Hamaguchi T, Taniguchi Y, Sakai K, et al. Significant association of
bility that affected individuals treated with cadaveric dura cadaveric dura mater grafting with subpial Abeta deposition and
meningeal amyloid angiopathy. Acta Neuropathol 2016;132:
many years previously could potentially transmit Aβ seeds. 313–315.
We provide new evidence that this transmission can result
7. Iwasaki Y, Imamura K, Iwai K, et al. Autopsied case of non-plaque-
in symptomatic disease during a patient’s lifetime and is type dura mater graft-associated Creutzfeldt-Jakob disease present-
not simply an incidental postmortem finding. If confirmed ing with extensive amyloid-beta deposition. Neuropathology 2018;
38:549–556.
in larger, more definitive epidemiological studies, our con-
8. Jaunmuktane Z, Quaegebeur A, Taipa R, et al. Evidence of amyloid-
clusions could have implications for public health precau- beta cerebral amyloid angiopathy transmission through neurosur-
tions, to avoid future clinical transmission and ensure safe gery. Acta Neuropathol 2018;135:671–679.
laboratory practices for handling tissues containing Aβ 9. Herve D, Porche M, Cabrejo L, et al. Fatal Abeta cerebral amyloid
pathology. angiopathy 4 decades after a dural graft at the age of 2 years. Acta
Neuropathol 2018;135:801–803.

10. Beck J, Pittman A, Adamson G, et al. Validation of next-generation

sequencing technologies in genetic diagnosis of dementia. Neuro-
biol Aging 2014;35:261–265.
Acknowledgment 11. Corovic A, Kelly S, Markus HS. Cerebral amyloid angiopathy associ-
G.B. receives funding from the National Institute of ated with inflammation: a systematic review of clinical and imaging
features and outcome. Int J Stroke 2018;13:257–267.
Health Research (NIHR; as an Academic Clinical Fellow)
12. Salvarani C, Morris JM, Giannini C, et al. Imaging findings of cerebral
and Rosetrees Trust. S.M. is an NIHR Senior Investiga- amyloid angiopathy, abeta-related angiitis (ABRA), and cerebral amy-
tor. D.J.W. receives research support from the Stroke loid angiopathy-related inflammation: a single-institution 25-year
experience. Medicine (Baltimore) 2016;95:e3613.
Association, British Heart Foundation, and Rosetrees
Trust. Some of this work was funded by the Medical 13. Piazza F, Greenberg SM, Savoiardo M, et al. Anti-amyloid beta auto-
antibodies in cerebral amyloid angiopathy-related inflammation:
Research Council UK (S.M.) and NIHR Biomedical implications for amyloid-modifying therapies. Ann Neurol 2013;73:
Research Centre at University College London Hospitals 449–458.

National Health Service Foundation Trust (S.M., S.B.). 14. Sperling RA, Jack CR Jr, Black SE, et al. Amyloid-related imaging
abnormalities in amyloid-modifying therapeutic trials: recommenda-
We thank Dr T. Hughes and C. Patel for their con- tions from the Alzheimer’s Association Research Roundtable Work-
tribution to the care of the patient described in Case group. Alzheimers Dement 2011;7:367–385.

February 2019 289

ANNALS of Neurology

15. Banerjee G, Alvares D, Bowen J, et al. Minimally symptomatic cere- 26. Rudge P, Jaunmuktane Z, Adlard P, et al. Iatrogenic CJD due to
bral amyloid angiopathy-related inflammation: three descriptive case pituitary-derived growth hormone with genetically determined incu-
reports. J Neurol Neurosurg Psychiatry 2019;90:113–115. bation times of up to 40 years. Brain 2015;138(pt 11):3386–3399.

16. Sevigny J, Chiao P, Bussiere T, et al. The antibody aducanumab 27. Muayqil T, Gronseth G, Camicioli R. Evidence-based guideline: diag-
reduces Abeta plaques in Alzheimer’s disease. Nature 2016;537: nostic accuracy of CSF 14-3-3 protein in sporadic Creutzfeldt-Jakob
50–56. disease: report of the guideline development subcommittee of the
American Academy of Neurology. Neurology 2012;79:1499–1506.
17. Carlson C, Estergard W, Oh J, et al. Prevalence of asymptomatic
vasogenic edema in pretreatment Alzheimer’s disease study cohorts 28. Rovelet-Lecrux A, Hannequin D, Raux G, et al. APP locus duplication
from phase 3 trials of semagacestat and solanezumab. Alzheimers causes autosomal dominant early-onset Alzheimer disease with cere-
Dement 2011;7:396–401. bral amyloid angiopathy. Nat Genet 2006;38:24–26.

18. Weller RO, Hawkes CA, Kalaria RN, et al. White matter changes in 29. Sleegers K, Brouwers N, Gijselinck I, et al. APP duplication is suffi-
dementia: role of impaired drainage of interstitial fluid. Brain Pathol cient to cause early onset Alzheimer’s dementia with cerebral amy-
2015;25:63–78. loid angiopathy. Brain 2006;129(pt 11):2977–2983.

30. Rovelet-Lecrux A, Frebourg T, Tuominen H, et al. APP locus duplica-

19. Antoine JC, Michel D, Bertholon P, et al. Creutzfeldt-Jakob disease
tion in a Finnish family with dementia and intracerebral haemor-
after extracranial dura mater embolization for a nasopharyngeal
rhage. J Neurol Neurosurg Psychiatry 2007;78:1158–1159.
angiofibroma. Neurology 1997;48:1451–1453.
31. Cabrejo L, Guyant-Marechal L, Laquerriere A, et al. Phenotype asso-
20. Defebvre L, Destee A, Caron J, et al. Creutzfeldt-Jakob disease after
ciated with APP duplication in five families. Brain 2006;129(pt 11):
an embolization of intercostal arteries with cadaveric dura mater sug-
2966–2976.
gesting a systemic transmission of the prion agent. Neurology 1997;
48:1470–1471. 32. Kasuga K, Shimohata T, Nishimura A, et al. Identification of indepen-
dent APP locus duplication in Japanese patients with early-onset Alz-
21. Eisele YS, Obermuller U, Heilbronner G, et al. Peripherally applied
heimer disease. J Neurol Neurosurg Psychiatry 2009;80:1050–1052.
Abeta-containing inoculates induce cerebral beta-amyloidosis. Sci-
ence 2010;330:980–982. 33. Llado A, Grau-Rivera O, Sanchez-Valle R, et al. Large APP locus
duplication in a sporadic case of cerebral haemorrhage. Neuroge-
22. Collinge J. Mammalian prions and their wider relevance in neurode- netics 2014;15:145–149.
generative diseases. Nature 2016;539:217–226.
34. Heath CA, Barker RA, Esmonde TF, et al. Dura mater-associated
23. Public Health England. Creutzfeldt-Jakob disease (CJD) biannual Creutzfeldt-Jakob disease: experience from surveillance in the UK.
update (February 2018). Accessed date: January 11, 2019. Available J Neurol Neurosurg Psychiatry 2006;77:880–882.
at: https://assets.publishing.service.gov.uk/government/uploads/system/
uploads/attachment_data/file/680709/hpr0518_CJD.pdf. 35. Ae R, Hamaguchi T, Nakamura Y, et al. Update: Dura mater graft-
associated Creutzfeldt-Jakob disease—Japan, 1975-2017. MMWR
24. Brown P, Preece M, Brandel JP, et al. Iatrogenic Creutzfeldt-Jakob Morb Mortal Wkly Rep 2018;67:274–278.
disease at the millennium. Neurology 2000;55:1075–1081.
36. Nakayama Y, Mineharu Y, Arawaka Y, et al. Cerebral amyloid angio-
25. Brooke FJ, Boyd A, Klug GM, et al. Lyodura use and the risk of iatro- pathy in a young man with a history of traumatic brain injury: a case
genic Creutzfeldt-Jakob disease in Australia. Med J Aust 2004;180: report and review of the literature. Acta Neurochir (Wien) 2017;159:
177–181. 15–18.

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